Radiolabeled diagnostic and therapeutic agents are used for the diagnosis and treatment of cancer and related conditions. To be effective, a diagnostic or therapeutic agent should be capable of localization at the site of interest, e.g., at a tumor site, in order to provide sufficient specificity.
Ideally, radiolabeled agents for cancer imaging and therapy should meet as many of the following criteria as possible: (i) be stable in blood following their administration in a subject; (ii) be taken up rapidly by tumors (T1/2 in circulation shorter than the decay half-life of the radionuclide); (iii) be retained for long periods of time within tumors (T1/2 in tumors shorter than the decay half-life of the radionuclide); (iv) be concentrated efficiently by tumors (i.e. high % ID/g); (v) be taken up minimally by normal tissue cells; (vi) have a short residence in normal tissues (i.e., short effective half-life in blood, bone marrow, and whole body); (vii) achieve high tumor-to-normal-tissue uptake ratios; and (viii) be labeled with an emitter whose decay characteristics are suitable for imaging (PET or SPECT) or radiotherapy. Additional desirable characteristics of a therapeutic agent include: (i) be labeled with an energetic particle emitter, (ii) attain an intratumoral distribution that is sufficiently uniform to match the range of the emitted particles (i.e. all tumor cells are within the range of the emitted particles), and (iii) achieve an intratumoral concentration that is sufficiently high to deposit a tumorcidal dose in every cell that is within the range of the emitted particle. Conventional reagents generally do not meet all these requirements, and, as a result, are ineffective for therapy or may cause side effects when administered to a subject.
One approach to this problem is known as Enzyme-Mediated Cancer Imaging and Therapy (EMCIT). In EMCIT, a water-soluble, radiolabeled prodrug is administered to the subject; when the prodrug reaches the tumor site, it is hydrolyzed to a water-insoluble form by an enzyme which is present within solid tumors at higher concentrations that those present in normal tissues (see, e.g., Ho et al., Bioconj. Chem. 13:357 (2002). The water-insoluble radiolabeled compound then precipitates in the extracellular space around the tumor cells, where its insolubility prevents further biodistribution. When the trapped compound is radiolabeled with a gamma or positron emitting radionuclide, it will enable the selective imaging (SPECT/PET) of tumors. On the other hand, when the trapped molecule is radiolabeled with an energetic alpha- or beta-particle-emitting radionuclide, it will irradiate the tumor mass and eradicate the tumor. See, e.g., U.S. Patent Application Publication 2003-0021791. However, while this approach can provide greater site specificity than conventional methods, improved properties of the water-soluble prodrug and the water-insoluble form would be desirable.